The following is a brief description of the physiology of asthma. The discussion is not meant to be complete and is provided only for understanding of the invention that follows. This summary is not an admission that any of the work described below is prior art to the claimed invention.
The term "asthma" originally meant "difficult breathing." It now refers to a number of diseases involving constriction of the airways. Intrinsic asthma is characterized by recurrent episodes of airway obstruction that resolve spontaneously or after treatment. The etiology of intrinsic asthma is unknown.
Extrinsic asthma is associated with hyperresponsiveness of the airways to a variety of inhaled stimuli. These stimuli have little or no effect on normal subjects. Clinical results obtained from bronchoalveolar lavage and lung biopsies show good correlation between infiltration of activated T helper cells and eosinophils and hyperresponsiveness of the lungs.
Asthma affects nearly 5% of the population in industrialized nations, yet it is underdiagnosed and undertreated. There is evidence that the incidence and prevalence of asthma are rising. These trends are occurring despite increases in the available therapies for asthma, which suggests that current methods of treating asthma are inadequate or not being utilized appropriately. Recently, it has been recognized that chronic asthma involves a characteristic inflammatory response in the airways.
Although it has long been acknowledged that fatal asthma is associated with inflammatory changes in the submucosal surfaces of the airways, it is now apparent that inflammation is present in patients with very mild asthma. Biopsies of patients have shown that infiltration of immune cells, especially eosinophils and lymphocytes, and epithelial shedding are prominent features. Further, there is a strong correlation between the degree of eosinophilia and the degree of bronchial hyperresponsiveness. Eosinophils are localized to areas of epithelial damage in the airways of patients. The basic proteins released by the eosinophils may be responsible for the damage observed in these patients. The role of mast cells and neutrophils in the disease is uncertain. Lymphocytes are present at the sites of tissue damage, but their role may be as mediators to amplify the eosinophilic response. In fact, interleukin-5, which is released by T-lymphocytes, is important in retaining and priming eosinophil action in the airway.
Mild, periodic episodes of bronchoconstriction can be managed by inhalation of .beta..sub.2 -adrenergic antagonists. Severe chronic asthma may require several agents including systemic administration of adrenocorticosteroids on a regular basis. Other treatments include theophylline (a smooth muscle relaxant and a bronchodilator; a strong CNS activator more potent than caffeine). Cromolyn Sodium, an inhibitor of degranulation of pulmonary mast cells by inhibiting release of inflammatory mediators. Therapeutic effects are prophylactic and no toxic side effects have been associated with these drugs.